Merestinib dihydrochloride

Merestinib dihydrochloride (LY2801653 dihydrochloride) is a potent, orally bioavailable c-Met inhibitor ( K i =2 nM) with anti-tumor activities. Merestinib dihydrochloride also has potent activity against MST1R (IC 50 =11 nM), FLT3 (IC 50 =7 nM), AXL (IC 50 =2 nM), MERTK (IC 50 =10 nM), TEK (IC 50 =63 nM), ROS1, DDR1/2 (IC 50 =0.1/7 nM) and MKNK1/2 (IC 50 =7 nM) In Vitro Merestinib (LY2801653) also inhibits MST1R (IC 50 =11 nM), AXL (IC 50 =2 nM), MERTK (IC 50 =10 nM), TYRO3 (IC50=28 nM), ROS1, PDGFRA (IC50=41 nM), FLT3 (IC 50 =7 nM), TEK (IC50=63 nM), DDR1/2 (IC 50 =0.1/7 nM) and MKNK1/2 (IC 50 =7 nM). Merestinib demonstrates effects on MET pathway-dependent cell scattering and cell proliferation. The mean IC 50 value (n=6 determinations) of Merestinib for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells is 35.2±6.9 nM and the IC 50 for MET auto-phosphorylation in S114 cells is 59.2 nM. Transfection with the MET variants confers growth-factor independence and treatment with Merestinib inhibits growth of these MET variant clones with an IC 50 ranging from 3-fold more potent (V1092I) to approximately 6-fold less potent (L1195V) compare with the growth inhibition of cells with the MET wild-type sequence. Merestinib (2, 5, and 10 μM) reduces the number of viable TFK-1 and SZ-1 cells in a dose and time dependent manner, and significant inhibits wound healing for TFK-1 and SZ-1 cell lines. Merestinib inhibits cell invasion in TFK-1 and SZ-1 cells in a concentration dependent manner. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo Merestinib (LY2801653) demonstrates anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. Merestinib (LY2801653) is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a pharmacodynamic residence time (K off ) of 0.00132 min -1 and t 1/2 of 525 min. Merestinib (LY2801653) treatment inhibits MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 (90 % target inhibition dose) of 7.4 mg/kg . Merestinib (LY2801653) (20 mg/kg) reduces TFK-1 tumor growth significantly relative to vehicle control. Merestinib (LY2801653) inhibits the growth of intra- and extrahepatic CCC xenograft tumors. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid IC50& Target:Ki: 2 nM (c-Met), IC50: 11 nM (MST1R), 7 nM (FLT3), 2 nM (AXL), 10 nM (MERTK), 63 nM (TEK), 0.1/7 nM (DDR1/2), 7 nM (MKNK1/2)

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